In humans, autoimmune disorders such as rheumatoid arthritis (RA) are characterized by increased inflammatory cytokine production including overproduction of TNFa. Many rheumatic disorders are also characterized by alterations in B cell subsets and autoantibody production. In RA, the administration of agents that neutralize TNFa promotes resolution of clinical symptoms and reductions in rheumatoid factor production. The success of anti-B cell therapies in RA underscores the importance of B cells to the pathogenesis of RA and highlights possible interconnections between the overproduction of TNFa and B cell abnormalities in rheumatic inflammatory diseases. In mice, the administration of inflammatory stimuli such as adjuvants or TNFa, induces the emigration of immature B cells from the bone marrow to the peripheral blood and spleen. These B cell emigrants have the characteristics of immature B cells and contain subpopulations that expand in colony forming assays, and subpopulations that express AID and have somatically mutated immunoglobulin genes despite their development outside germinal centers. Importantly, the administration of adjuvants such as Freund's or pristane to susceptible rodent strains is associated with the development of arthritis and lupus-like symptoms and the development of autoantibodies. B cells with immature phenotypes accumulate in the synovial tissue of RA patients. Therefore, although speculative, we believe that there may be an important relationship between TNFa-induced pre-B cell bone marrow emigrants and the subsequent development of autoimmunity. We also believe that this population of peripheral pre-B cells may represent the precursors for populations of B cells identified in X-linked hyper IgM syndrome patients that contain somatically mutated immunoglobulin genes despite the absence of germinal centers in these patients. Patients with hyper IgM syndrome develop autoantibodies and autoimmune syndromes. Studies on TNFa-induced pre-B cell bone marrow emigrants have not been performed in humans. Therefore, we will determine whether similar populations of pre-B cells can be detected in human peripheral blood and we will characterize these B cells phenotypically and functionally. We believe that B cell populations similar to TNFa-induced pre-B cell bone marrow emigrants in mice will be expanded in human cord blood samples, in peripheral blood in human subjects administered adjuvant, and in patients with RA. We will also determine whether anti-TNFa therapy is associated with reductions in peripheral populations of TNFa- induced pre-B cell bone marrow emigrants in RA patients. [unreadable] [unreadable] [unreadable]